Some specific lipid molecules in the brain act as signaling molecules, neurotransmitters, or neuromodulators, by binding to specific G protein-coupled receptors (GPCR) for neurolipids. One such receptor, sphingosine 1-phosphate receptor subtype 1 (S1P₁), is coupled to G_i/o proteins and is involved in cell proliferation, growth, and neuroprotection. S1P₁ constitutes an interesting target for neurodegenerative diseases like multiple sclerosis and Alzheimer's disease (AD), in which changes in the sphingolipid metabolism have been observed. This study analyzes S1P₁ receptor-mediated activity in healthy brains and during AD progression using postmortem samples from controls and patients at different Braak's stages. Additionally, the distribution of S1P₁ receptor activity in human brains is compared to that in commonly used rodent models, rats and mice, through functional autoradiography, measuring [³⁵S]GTPγS binding stimulated by the S1P₁ receptor selective agonist CYM-5442 to obtain the distribution of functional activity of S1P₁ receptors. S1P₁ receptor-mediated activity, along with that of the cannabinoid CB₁ receptor, is one of the highest recorded for any GPCR in many gray matter areas of the brain, reaching maximum values in the cerebellar cortex, specific areas of the hippocampus and the basal forebrain. S1P₁ signaling is crucial in areas that regulate learning, memory, motor control, and nociception, such as the basal forebrain and basal ganglia. In AD, S1P₁ receptor activity is increased in the inner layers of the frontal cortex and underlying cortical white matter at early stages, but decreases in the hippocampus in advanced stages, indicating ongoing brain impairment. Importantly, we identified significant correlations between S1P₁ receptor activity and Braak stages, suggesting that S1P₁ receptor dysfunction is associated to disease progression, particularly in memory-related regions. The S1P signaling via S1P₁ receptor is a promising neurological target due to its role in key neurophysiological functions and its potential to modify the progression of neurodegenerative diseases. Finally, rats are suggested as a preferred experimental model for studying S1P₁ receptor-mediated responses in the human brain.